Deciding on an Agent for Prostate Cancer Involves Careful Consideration of Prior Therapy

Anthony A. Meluch, MD

Anthony A. Meluch, MD, medical oncologist, Tennessee Oncology, discussed treatment options for high-risk adenocarcinoma of the prostate based on the case of a 75-year-old patient during a Targeted Oncology Case-Based Peer Perspectives event.

Targeted Oncology™: Do you agree with the initial choice of treatment in this patient?

MELUCH: If you classify this patient based on local disease—low, intermediate, favorable, unfavorable high, or very high—he falls into the high category. A caveat for these patients, especially this typically older group of patients, is you need to have a look at the person and make an informed decision. Could you have done surgery? Yes, but in a 75-year-old, is that what you want to do?

The radiation was a good option, and 18 months is standard. There are a variety of trials [examining the optimal timing of radiation at] 6 versus 18 versus 36 months, and 18 months is typical. [You may be able] to differentiate in this group of patients to have further benefit beyond that. I think he had a good treatment plan. I would also use an osteoclast agent.

For metastatic disease, which frontline systemic treatment are you most likely to offer this patient? Docetaxel is a good drug, but you have the FIRSTANA trial [NCT01308567],1 which compared docetaxel versus cabazitaxel [Jevtana] at 20 mg/m² and 25 mg/m². Across the board, survival analysis was quite equal; it was a noninferiority outcome in the end. There were slightly higher response rates with docetaxel, but it was also a bit more toxic.

When it comes to targeted therapy, whether we use enzalutamide [Xtandi] or abiraterone acetate [Zytiga], you have to analyze your patient. They have different toxicity profiles, and abiraterone requires significant compliance with prednisone. In somebody who has significant neurologic dysfunction, there’s a small but slight risk of problems with enzalutamide. With abiraterone, if they have diabetes and [other endocrine] issues, maybe that would [help inform whether to use] one agent or the other. We don’t know that one is better than the other because they haven’t been compared head-to-head.

Is there an optimal sequence of abiraterone and enzalutamide?

If we can get [targeted androgen deprivation therapy] approved for those patients with limited metastatic disease, I will use it. There is a phase 2 trial in which patients got either enzalutamide or abiraterone first and then they crossed over to the other therapy at progression. In that trial, up-front abiraterone had a slightly higher response rate, both by RECIST and PSA, but enzalutamide had a higher second response rate as a salvage. In the end, the overall survival and results were almost identical.²

Abiraterone typically does not have a lot of activity after enzalutamide. The best trial of enzalutamide had about a 20% response rate. If patients have androgen receptor splice variant 7 [AR-V7]–positive disease, they won’t respond to either agent up front. But patients can develop it, so if it’s not an emergency, you could run the test once they failed one of those drugs to see if they’d benefit or not.

In this patient, I’d probably use a second-generation androgen receptor inhibitor and consider the radiation.

What do you think of the choice of docetaxel in hormone-refractory disease?

If you look at docetaxel, the TAX 327 trial [NCT00268593] investigated weekly docetaxel for 5 weeks with 1 week off, or docetaxel every 3 weeks, or mitoxantrone and prednisone every 3 weeks. I raised the issue that with weekly docetaxel, once you get more than 1 week off, you aren’t going to tolerate it. When you look at the data, the highest response rate was in the weekly docetaxel group. Unfortunately, they had more people drop off the trial on that [regimen] because of skin toxicity and fatigue. It lessened the benefit, and the survival benefit favored the [3-week dosing schedule]. You could do dose regimens and modifications to give these people therapy.³

What factors do you consider when deciding on treatment for this patient?

I look at their overall [health] status. My last 3 referrals from urologists all came in wheelchairs. You’ve got to make wise decisions there.

If I need a rapid response and they have a low PSA but a lot of disease, a high-grade disease, I’m looking more at chemotherapy than an AR-targeted therapy. The likelihood of [one of those approaches] working is higher. If it’s a slow-developing tumor and they don’t have a lot of disease, getting the AR-V7 mutation test and waiting until clearing is a good option.

What do you think of the results of the poll? What would you recommend?

I probably wouldn’t use abiraterone. I wouldn’t use Radium 223 [Xofigo], at least not up front, especially with a patient who has lymph node and soft tissue metastasis. At this time, it would be excellent to check for his genetic assay to see if he has one of the DDR [DNA damage repair] gene abnormalities. Cabazitaxel is also reasonable, especially at the dose of 20 mg/m², despite some of his difficulties with docetaxel.

What data support the use of cabazitaxel to treat this patient at this point?

The CARD trial [NCT02485691] is a phase 4 study, or a postmarketing study, of patients who fit the description of this patient. It’s a multicenter, international trial of all patients who had metastatic castrate-resistant prostate cancer who had prior docetaxel and received 1 AR-targeted agent, either enzalutamide or abiraterone. They had to have progressed within 12 months of getting therapy. They had to have a reasonable ECOG performance status of 2 or less to get on the trial.^4,5

Patients were randomized 1:1 to get cabazitaxel with prednisone at 25 mg/m² or abiraterone/enzalutamide; the drug that they got was the one that they didn’t get previously. If they were on enzalutamide, they got abiraterone and vice versa. The primary end point was radiographic progression-free survival [PFS] with secondary end points of overall survival [OS] and PSA response. They also looked at pain control; time to other serious events, such as skeletal; safety; and quality of life. Some of the quality-of-life data just came out. They stratified patients by a performance status, 1 or less versus 2, and the time to progression on second-generation antiandrogen therapy, 6 months or less or between 6 and 12 months. They also stratified patients by the timing of their second-generation antiandrogen therapy, before docetaxel or after.

At baseline, typical patients treated on the trial were in their early 70s. The pain score [at baseline] is slightly higher in the abiraterone and enzalutamide arm, and the Gleason scores are slightly higher there as well. By their prior second-generation antiandrogen therapy, there are no major differences.

Which agent induced greater efficacy in patients?

The primary end point of radiographic PFS showed a statistically significant improvement with cabazitaxel versus abiraterone/enzalutamide, at 8.0 versus 3.7 months, respectively [HR, 0.54; 95% CI, 0.40-0.73; P < .0001].

Looking at a forest plot of radiographic PFS for all the patients based on their different characteristics, it’s easy to see that almost every criterion has a statistically significant effect. They didn’t find the group of patients that may not have benefited with this treatment, including those defined by their initial statistical analysis.

Similarly, time to the first symptomatic skeletal event is less statistically significant versus those who got a second round of a different second-generation antiandrogen agent, since you have the cabazitaxel right on the edge, with a P value of 0.05.

What are the toxicity concerns with cabazitaxel?

We know there’s toxicity with chemotherapy, especially looking at our patient who didn’t do as well as he could have with docetaxel. If you look at all AEs [adverse events] on both arms, almost all patients experienced something. About 50% got at least a grade 3 or 4 event. Serious AEs occurred in over a third of patients in both arms of this trial. Cabazitaxel did lead to a higher likelihood of discontinuation of treatment, at about 20% versus just under 10% for the other arm.

How was the health-related quality-of-life in CARD?

The investigators looked at quality of life with the FACT-P [Functional Assessment of Cancer Therapy—Prostate] score. Across every measure, a couple of factors were break-even between arms. Overall, this cabazitaxel group did better than those on the hormone therapy in the second line. It added to data that this certainly could be a drug to consider for such patients.

^References:

^{1. Oudard S, Fizazi K, Sengel.v L, et al. Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant prostate cancer: a randomized phase III trial-FIRSTANA. J Clin Oncol. 2017;35(28):3189-3197. doi:10.1200/JCO.2016.72.1068}

^{2. Khalaf DJ, Annala M, Taavitsainen S, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 2019;20(12):1730-1739. doi:10.1016/S1470-2045(19)30688-6}

^{3. Tannock IF, de Wit R, Berry WR, et al; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512. doi:10.1056/NEJMoa040720}

^{4. de Wit R, de Bono J, Sternberg CN, et al; CARD Investigators. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506‐2518. doi:10.1056/NEJMoa1911206}

^{5. de Wit R, Kramer G, Eymard J, et al. CARD: randomized, open-label study of cabazitaxel (CBZ) vs abiraterone (ABI) or enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394 chronic lymphocytic leukemia}